Abstract Fusionpositivesarcoma(FPS)occursin1,100newpatientsunder18-yearsannuallyintheUnitedStates. AdvancesinunderstandingthemolecularphenotypesofFPSinchildrenhaveoccurredbutanticipationthat theseadvanceswouldleadtosignificantchangesinpatientcarehavenotbeenrealized.Failureofmodern therapiesinhigh-riskchildrendemandsanothersystemofexplorationbeyondmolecularandgenomestudies, tofurtheranunderstandingofpotentiallyclinicallytargetablepathwaysthatwouldallowcategorizationof patients,elucidationoftreatmentresponseandpersonalizationoftherapy.Sophisticatedbiomarkers evaluatingresponsetotherapyinFPSinchildrenhavenotbeensuccessfullydevelopedtoallowtreatment relateddecisions.Whilemultifactorialthisisinpartbecauseoflimitedsensitivityandspecificityofanalytes, absenceoftumorspecimensinpatientsforwhomradiationisdeliveredtoachievelocaltumorcontroland significanttimebetweeninitiationoftherapyandsubsequentsurgerytoresecttumors.Anunderstandingofthe metabolicreprogramminginFPS,theoverallstudyobjective,holdsthepromisetoovercomesomeofthese limitations.Specifically,itisknownthatmostcancercells,includingFPS,aredependentonincreasedglucose uptaketoprovideenergyandmacromolecularprecursorsforcellsurvivalandgrowth.Itisalsoknownthat cancerrelatedmetabolicvulnerabilitiesaredifferentincultureandin-vivo.Thissuggeststhatin-vivostudies areacriticalelementtoacomprehensiveexaminationofthemetabolicsignaturesofFPS.UTSouthwesternis oneofaveryfewcentersworldwide,wherethedeliveryof13C,astableheavyisotopeofcarbon,hasbeen optimizedtostudymetabolicfluxinlivingtumorsinchildren.13Ciseasilyidentifiablefrom12Cbyexperimental methods,12Cbeingthepredominantisotopeofcarboninnature.Consequently,thisallowssophisticatedand dynamicexaminationoftheutilizationofglucoseinmetabolicallyactivepathwaysincancercellswhentumor specimensarestudiedfrompatientswhoreceiveconcomitant13Cinfusion.Thisisanon-toxiccompoundin humansandalreadythedeliveryhasbeendevelopedandidealdoseidentified,forchildrentreatedatUT SouthwesternandChildren?sMedicalCenterDallas.Inaim1ofthisproposalwewillexaminethemetabolic signaturesofFPSinchildrendiagnosedandtreatedover2-yearsatUTSouthwesternandChildren?sMedical CenterDallas.Inaim2wewillstudyinparallelpre-clinicalmodelsystemsofFPS.Theselattersystemswill includemouse-modelsofpatientderivedtumors,knownaspatientderivedxenografts,whereinwewillbeable tostudymetabolicsignaturesundertheeffectofcommonlyusedtherapiesandastumorsevolveovertime. Suchparallelandcomplimentarystudieswillprovidethefirst-evercomprehensiveevaluationofacritically importantandbiologicallyrelevantcellularpathwayinFPSinchildrenandoffersthepotentialtoaddress severallimitationsindesigningeffectiveandpersonalizedtreatmentsforpatientsforwhomcurrenttherapies continuetofail.